Abstract Alzheimer's disease is a condition in which brain clearance of toxic peptides such as amyloid beta (A?) is known to be impaired. Determining the specific mechanisms by which brain clearance becomes impaired will open up therapeutic opportunities for attenuating or preventing Alzheimer's disease. The field has focused considerable attention on vascular risk factors such as A? transport at the blood-brain barrier, but this knowledge has not yet led to breakthrough treatments. Despite some progress, the problem of impaired A? clearance has not been solved. Thus, there is a need to consider alternative routes or mechanisms of clearance. The recently discovered meningeal lymphatic system is a prime candidate for the missing link between impaired A? clearance and Alzheimer's disease. This previously unrecognized network of intracranial drainage vessels is located in the meninges, or membranes surrounding the brain, and actively participates in clearance of fluid and solutes from the brain. For many years, it was known that substances injected into the brain make their way to the lymphatic drainage system in the head and neck, but the anatomical connections largely remained a black box. Before the discovery of A?, researchers also found that ligation of cervical lymphatics resulted in cognitive impairment, but a direct link between lymphatic drainage and dementia was never established. Correlative data now suggest that the meningeal lymphatic system is involved in maintenance of brain health by managing the removal of endogenous waste to the systemic circulation. Yet there is no clear functional link between meningeal lymphatics and major pathological features of Alzheimer's disease, and it is furthermore unclear how lymphatic function would become compromised during disease initiation or progression. My hypothesis is that pathological changes develop in the meningeal lymphatics during the aging process, thereby promoting initiation or progression of Alzheimer's disease. To test this hypothesis, my lab has adapted the best available rat model of Alzheimer's disease which carries all the hallmarks of the human disease. This transgenic Alzheimer's disease rat was cross-bred with another rat expressing a fluorescent marker protein in the lymphatic vasculature, so the full extent of vessels is visualized in exquisite detail. Using this hybrid triple transgenic rat model, the hypothesis will be tested by first determining a direct causal relationship between failure of the meningeal lymphatic system and the development of Alzheimer's disease. This will be accomplished in Specific Aim #1 which will modulate its function using novel surgical approaches to impair the drainage exit routes of the lymphatic vasculature. In order to define the precise anatomical localization of the meningeal lymphatic system in Alzheimer's disease progression, which will enable drug development, Specific Aim #2 will determine the time course and magnitude of structural changes in meningeal lymphatic vessels during progression of Alzheimer's disease. My career development and training plan will provide the resources and skills for me to establish the specific role of the meningeal lymphatic system in progression of Alzheimer's pathology and cognitive impairment, and will pave my pathway to independence in the new field of lymphatic neurovascular biology.